10-89206682-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003956.4(CH25H):​c.611A>G​(p.His204Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CH25H
NM_003956.4 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.19
Variant links:
Genes affected
CH25H (HGNC:1907): (cholesterol 25-hydroxylase) This is an intronless gene that is involved in cholesterol and lipid metabolism. The encoded protein is a membrane protein and contains clusters of histidine residues essential for catalytic activity. Unlike most other sterol hydroxylases, this enzyme is a member of a small family of enzymes that utilize diiron cofactors to catalyze the hydroxylation of hydrophobic substrates. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3838396).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CH25HNM_003956.4 linkuse as main transcriptc.611A>G p.His204Arg missense_variant 1/1 ENST00000371852.4 NP_003947.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CH25HENST00000371852.4 linkuse as main transcriptc.611A>G p.His204Arg missense_variant 1/1 NM_003956.4 ENSP00000360918 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 06, 2023The c.611A>G (p.H204R) alteration is located in exon 1 (coding exon 1) of the CH25H gene. This alteration results from a A to G substitution at nucleotide position 611, causing the histidine (H) at amino acid position 204 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.34
BayesDel_addAF
Uncertain
0.058
T
BayesDel_noAF
Benign
-0.15
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.35
T
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Benign
0.72
T
M_CAP
Benign
0.058
D
MetaRNN
Benign
0.38
T
MetaSVM
Uncertain
-0.091
T
MutationAssessor
Benign
2.0
M
MutationTaster
Benign
0.74
N
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-2.2
N
REVEL
Uncertain
0.58
Sift
Benign
0.34
T
Sift4G
Benign
0.34
T
Polyphen
0.72
P
Vest4
0.17
MutPred
0.68
Gain of methylation at H204 (P = 0.0283);
MVP
0.84
MPC
1.1
ClinPred
0.86
D
GERP RS
3.8
Varity_R
0.14
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-90966439; API